Viewpoints

The Role of Reactive Oxygen Species (ROS) in Persistent Pain

Mechanisms that underlie persistent (i.e., chronic) pain are different from those that underlie acute pain. Recent findings
seem to indicate that superoxide (SO) is a mediator of persistent pain that accompanies inflammation. Other reactive oxygen
species (ROS) might also participate in persistent pain. Wang and colleagues, in the Journal of Pharmacology and Experimental Therapeutics, found that SO contributes to hyperalgesic responses that can be ameliorated by the addition of a compound that mimics the
enzymatic function of superoxide dismutase (SOD). SO can also combine with nitric oxide to form peroxynitrite, which inhibits
the catalytic function of SOD. Expanded research on ROS as pain mediators should lead to better drugs for the management of
chronic pain and help further elucidate the different mechanisms involved in chronic vs acute pain.

Sándor Damjanovich,

Rezsó Gáspár,

and György Panyi

An Alternative to Conventional Immunosuppression: Small-Molecule Inhibitors of Kv1.3 Channels

The advent of clinically useful immunosuppressive drugs that block T-cell activation has given hope to many with autoimmune
disorders or organ transplants. These drugs, however, are not without potentially life-threatening side effects, including
kidney disease and increased incidence of infection or cancer. The identification of ion channels in T cells has raised the
possibility that channel blockers exhibiting high specificity might become new therapeutics in the never-ending search for
better immunosuppressants. Recent results published in Molecular Pharmacology have characterized new psoralen-derived compounds that specifically block the Kv3.1 channel in T effector (TEM) cells while sparing with the activation of naïve or T central memory cells. Thus, TEM cell–mediated autoimmune diseases such as multiple sclerosis or Type I diabetes mellitus might be successfully treated by
these new compounds.

Tomoshige Kino and

George P. Chrousos

Combating Atherosclerosis With LXRα And PPARα Agonists: Is Rational Multitargeted Polypharmacy the Future of Therapeutics
in Complex Diseases?

The development of atherosclerosis can, in the absence of intervention, lead to cardiovascular disease, which is responsible
for the demise of more Americans per year than any other disease. Beyer and colleagues report, in the Journal of Pharmacology and Experimental Therapeutics, that treating mice with a liver X receptor (LXR) agonist increases not only the concentration of circulating high-density
lipoprotein (HDL) but also, unfortunately, that of circulating triglycerides. When doubly treated with LXR agonists together
with peroxisome proliferator–activated receptor α(PPARα) agonists, mice exhibited reduced concentrations of circulating triglycerides
(but interestingly, triglyceride concentrations in the liver were not reduced) while their HDL concentrations remained elevated.
The authors suggest that activation of both receptors, through the development and use of LXRα–PPARα dual agonists, might
become a useful therapy to bolster HDL levels while simultaneously suppressing circulating triglycerides in patients.

Reviews

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Jorge A. Quiroz,

Todd D. Gould,

and Husseini K. Manji

MOLECULAR EFFECTS of lithium

Although the usefulness of lithium in the treatment of bipolar affective disorder was discovered over fifty years ago, only
recently have many of the molecular targets for lithium’s action been identified, including glycogen synthase kinase-3 (GSK-3)
and neurotrophic signaling cascades. These observations may lead to a new understanding of the underpinnings of bipolar disorder
and will likely support the use of lithium in the management and treatment of neurodegenerative disorders. Multiple lines
of investigation have established lithium’s direct effects on several phosphatases, kinases, and other enzymes, and have also
indicated lithium’s indirect effects on downstream targets, including adenylate cyclase, the phosphoinositol cascade and protein
kinase C, and arachidonic acid metabolism. There is also experimental momentum behind the hypothesis that lithium mediates
neurotrophic effects.

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C. Shun Wong and

Albert J. Van der Kogel

MECHANISMS OF RADIATION INJURY TO THE CENTRAL NERVOUS SYSTEM: IMPLICATIONS FOR NEUROPROTECTION

Owing to the difficulty of getting drugs across the blood–brain barrier, the treatment of various cancers of the brain range
from tumor resection (where possible) to radiation therapy. Unfortunately, irradiation of tumors also involves the irradiation
of surrounding normal brain tissue, and radiation injury of the central nervous system (CNS) has severe clinical consequences.
Clonogenic apoptosis is not the only mode of cell death in the CNS after radiation therapy; secondary injury leading to neural
cell death arises from alterations to the microenvironment as mediated by hypoxia/ischemia and inflammation. New research
now raises the possibility of reversible components in the injury response and may lead the way to novel neuroprotective interventions.
In particular, cytokine cascades and stress responses associated with radiation-associated damage provide important targets
for further investigations.

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Jerry J. Buccafusco

Neuronal Nicotinic Receptor Subtypes: DEFINING THERAPEUTIC TARGETS

Although neuropharmacologists have fervently sought ligands to target most classes of neuroreceptors, the cholinergic systems
have for the past few decades been relatively exempt from therapeutically biased investigations. This unfortunate situation
now seems to be improving, however, particularly with the discovery of multiple subtypes of nicotinic cholinergic receptors.
Several nicotine-derived compounds have been synthesized, and their efficiency in modulating nicotinic receptor subtypes has
led to the development of several experimental drugs for treatment of pain, neurodegenerative diseases, and psychiatric conditions
that involve cognitive impairment. Beyond the race that has been initiated to bring nicotinic drugs to market, these new compounds
have in some instances established themselves as experimental tools in the study of cholinergic functions.